Disorders of Blood Pressure Regulation—Role of Catecholamine Biosynthesis, Release, and Metabolism
Pathogenesis of Hypertension: Genetic and Environmental Factors (DT O’Connor, Section Editor)
First Online: 09 November 2011 DOI:
Cite this article as: Currie, G., Freel, E.M., Perry, C.G. et al. Curr Hypertens Rep (2012) 14: 38. doi:10.1007/s11906-011-0239-2 Abstract
Catecholamines (epinephrine and norepinephrine) are synthesised and produced by the adrenal medulla and postganglionic nerve fibres of the sympathetic nervous system. It is known that essential hypertension has a significant neurogenic component, with the rise in blood pressure mediated at least in part by overactivity of the sympathetic nervous system. Moreover, novel therapeutic strategies aimed at reducing sympathetic activity show promise in the treatment of hypertension. This article reviews recent advances within this rapidly changing field, particularly focusing on the role of genetic polymorphisms within key catecholamine biosynthetic enzymes, cofactors, and storage molecules. In addition, mechanisms linking the sympathetic nervous system and other adverse cardiovascular states (obesity, insulin resistance, dyslipidaemia) are discussed, along with speculation as to how recent scientific advances may lead to the emergence of novel antihypertensive treatments.
Keywords Epinephrine Norepinephrine Sympathetic nervous system Hypertension Catecholamines Chromogranins Catestatin Reactivity TRPM4 Target organ effects References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Esler M, Ferrier C, Lambert G, et al. Biochemical evidence of sympathetic hyperactivity in human hypertension. Hypertension. 1991;17(4 Suppl):29–35.
Newcombe CP, Shucksmith HS, Suffern WS. Sympathectomy for hypertension; follow-up of 212 patients. Brit Med J. 1959;1:142–4.
• Esler MD, Krum H et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010, 376:1903–9.
This study illustrates the safety and blood pressure–lowering effects of renal “sympathectomy” and offers an exciting alternative treatment strategy for resistant hypertension.
Julius S, Krause L, Schork NJ, et al. Hyperkinetic borderline hypertension in Tecumseh, Michigan. J Hypertens. 1991;9:77–84.
Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998;31:68–72.
Seravalle G, Quarti-Trevano F, Dell’Oro R, et al. Sympathetic, baroreflex and metabolic abnormalities in the optimal, normal and high blood pressure state. J Hypertens. 2010;28:e437.
Flaa A, Eide IK, Kjeldsen SE, Rostrup M. Sympathoadrenal stress reactivity is a predictor of future blood pressure: an 18-year follow-up study. Hypertension. 2008;52:336–41.
• Hassellund SS, Flaa A, Sandvik L, Kjeldsen SE, Rostrup M. Long-term stability of cardiovascular and catecholamine responses to stress tests: an 18-year follow-up study. Hypertension 2010, 55:131–6.
This was the first study to illustrate the long-term stability of stress-mediated cardiovascular reactivity. It adds weight to the hypothesis that altered stress responses are implicated in the development of hypertension.
Beetz N, Harrison MD, Brede M, et al. Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice. J Clin Invest. 2009;119:3597–612.
Flatmark T. Catecholamine biosynthesis and physiological regulation in neuroendocrine cells. Acta Physiol Scand. 2000;168:1–17.
Rao F, Zhang L, Wessel J, et al. Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo. Circulation. 2007;116:993–1006.
Zhang K, Zhang L, Rao F, et al. Human tyrosine hydroxylase natural genetic variation: delineation of functional transcriptional control motifs disrupted in the proximal promoter. Circ Cardiovasc Genet. 2010;3:187–98.
Nielsen SJ, Jeppesen J, Torp-Pedersen C. Tyrosine hydroxylase polymorphism (C-824T) and hypertension: a population-based study. Am J Hypertens. 2010;23:1306–11.
•• Gu Y, Zhang K, Biswas N et al. Urocortin 2 lowers blood pressure and reduces plasma catecholamine levels in mice with hyperadrenergic activity. Endocrinology 2010, 151:4820–9.
This important study highlights the future therapeutic potential of manipulating plasma urocortin 2 in hypertension.
Chen Y, Wen G, Rao F, et al. Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure. J Hypertens. 2010;28:76–86.
Ohlstein EH, Kruse LI, Ezekiel M, et al. Cardiovascular effects of a new potent dopamine beta-hydroxylase inhibitor in spontaneously hypertensive rats. J Pharmacol Exp Ther. 1987;241:554–9.
Chen Y, Zhang K, Wen G, et al. Human dopamine beta-hydroxylase promoter variant alters transcription in chromaffin cells, enzyme secretion, and blood pressure. Am J Hypertens. 2011;24:24–32.
Videen JS, Mezger MS, Chang YM, O’Connor DT. Calcium and catecholamine interactions with adrenal chromogranins. Comparison of driving forces in binding and aggregation. J Biol Chem. 1992;267:3066–73.
Kim T, Tao-Cheng JH, Eiden LE, Loh YP. Chromogranin A, an “on/off” switch controlling dense-core secretory granule biogenesis. Cell. 2001;106:499–509.
Mahapatra NR, O’Connor DT, Vaingankar SM, et al. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest. 2005;115:1942–52.
O’Connor DT. Plasma chromogranin A. Initial studies in human hypertension. Hypertension. 1985;7:I76–9.
Takiyyuddin MA, Parmer RJ, Kailasam MT, et al. Chromogranin A in human hypertension. Influence of heredity. Hypertension. 1995;26:213–20.
Chen Y, Rao F, Rodriguez-Flores JL, et al. Naturally occurring human genetic variation in the 3'-untranslated region of the secretory protein chromogranin A is associated with autonomic blood pressure regulation and hypertension in a sex-dependent fashion. J Am Coll Cardiol. 2008;52:1468–81.
Salem RM, Cadman PE, Chen Y, et al. Chromogranin A polymorphisms are associated with hypertensive renal disease. J Am Soc Nephrol. 2008;19:600–14.
Grobecker G, Roizen MF, Weise V, Saavedra JM, Kopin IJ. Letter: sympathoadrenal medullary activity in young, spontaneously hypertensive rats. Nature. 1975;258:267–8.
Jirout ML, Friese RS, Mahapatra NR, et al. Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive rat. Hum Mol Genet. 2010;19:2567–80.
Vaingankar SM, Li Y, Corti A, et al. Long human CHGA flanking chromosome 14 sequence required for optimal BAC transgenic “rescue” of disease phenotypes in the mouse Chga knockout. Physiol Genomics. 2010;41:91–101.
Vaingankar SM, Li Y, Biswas N, et al. Effects of chromogranin A deficiency and excess in vivo: biphasic blood pressure and catecholamine responses. J Hypertens. 2010;28:817–25.
Helle KB, Corti A, Metz-Boutigue MH, Tota B. The endocrine role for chromogranin A: a prohormone for peptides with regulatory properties. Cell Mol Life Sci. 2007;64:2863–86.
Mahata SK, O’Connor DT, Mahata M, et al. Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist. J Clin Invest. 1997;100:1623–33.
O’Connor DT, Kailasam MT, Kennedy BP, et al. Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension. J Hypertens. 2002;20:1335–45.
Dev NB, Gayen JR, O’Connor DT, Mahata SK. Chromogranin A and the autonomic system: decomposition of heart rate variability and rescue by its catestatin fragment. Endocrinology. 2010;151:2760–8.
Rao F, Wen G, Gayen JR, et al. Catecholamine release-inhibitory peptide catestatin (chromogranin A (352-372)): naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension. Circulation. 2007;115:2271–81.
Fung MM, Salem RM, Mehtani P, et al. Direct vasoactive effects of the chromogranin A (CHGA) peptide catestatin in humans in vivo. Clin Exp Hypertens. 2010;2010(32):278–87.
Gill BM, Barbosa JA, Dinh TQ, Garrod S, O’Connor DT. Chromogranin B: isolation from pheochromocytoma, N-terminal sequence, tissue distribution and secretory vesicle processing. Regul Peptides. 1991;33:223–35.
Zhang K, Rao F, Rana BK, et al. Autonomic function in hypertension; role of genetic variation at the catecholamine storage vesicle protein chromogranin B. Circ Cardiovasc Genet. 2009;2:46–56.
• Zhang K, Rao F, Wang L et al. Common functional genetic variants in catecholamine storage vesicle protein promoter motifs interact to trigger systemic hypertension. J Am Coll Cardiol 2010, 55:1463–75.
This study illustrates that functionally significant SNPs in the CHGB promoter influence blood pressure in both European and African populations.
Flockerzi V. An introduction on TRP channels. Handbook Exp Pharmacol. 2007;179:1–19.
Nilius B. TRP channels in disease. Biochimica Biophys Acta. 2007;1772:805–12.
•• Mathar I, Vennekens R, Meissner M et al. Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice. J Clin Invest 2010, 120:3267–79.
This elegant study identified in mice a novel gene that plays a role in hypertension with increased sympathetic tone.
Lambert E, Lambert G. Stress and its role in sympathetic nervous system activation in hypertension and the metabolic syndrome. Curr Hypertens Rep. 2011;2:327–34.
Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54:690–7.
Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens. 2010;23:1052–60.
Greenfield JR, Miller JW, Keogh JM, et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;2009(360):44–52.
Ni XP, Butler AA, Cone RD, Humphreys MH. Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones. J Hypertens. 2006;24:2239–46.
Grassi G, Padmanabhan S, Menni C, et al. Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population. J Hypertens. 2011;29:1121–7.
Wirtz PH, Ehlert U, Bartschi C, Redwine LS, von Kanel R. Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response. Metabolism. 2009;58:30–7.
Grassi G, Seravalle G, Quarti-Trevano F. The ‘neuroadrenergic hypothesis’ in hypertension: current evidence. Exp Physiol. 2010;95:581–6.
Levick SP, Murray DB, Janicki JS, Brower GL. Sympathetic nervous system modulation of inflammation and remodeling in the hypertensive heart. Hypertension. 2010;55:270–6.
Li G, Xu J, Wang P, Velazquez H, et al. Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation. 2008;117:1277–82.
Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81.
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